The presence of optically active α-hydroxylcarbonyl moieties as well as 1,2-diols in many biologically active natural products motivated numerous research into finding new routes to provide better stereocontrol for these synthetically useful synthons. Asymmetric α-hydroxylation of enolates and the Sharpless asymmetric dihydroxylation of olefins are some methods to synthesize these compounds. The year 2000 saw a renaissance of organocatalysis, and since then organocatalysis has emerged as an extremely useful tool for the preparation of enantiomerically pure compounds. Operational simplicity, availability and the non-toxicity of the organic catalysts compared to the corresponding transition-metal species, as well as its high efficiencies and selectivities attained in many organocatalytic transformations made this methodology very attractive for the formation of enantiomerically pure compounds.
In 2003, Zhong (Angew. Chem., Int. Ed. (2003) 42, 4247), MacMillan (S. P. Brown et al., J. Am. Chem. Soc. (2003) 125, 10808) and Hayashi (Y. Hayashi et al., Tetrahedron Lett. (2003) 44, 8293) independently reported the direct proline-catalyzed α-aminoxylation of aldehydes with nitrosobenzene and the usefulness of this reaction was demonstrated in the synthesis of several biologically active compounds (S. P. Kotkar et al., Tetrahedron: Asymmetry (2007) 18, 1795; S. P. Kotkar et al., Tetrahedron: Asymmetry (2007) 18, 1738; S. P. Kotkar & A. Sudalai, Tetrahedron Lett. (2006) 47, 6813; S. V. Narina & A. Sudalai, Tetrahedron Lett. (2006) 47, 6799; S. G. Kim & T. H. Park, Tetrahedron Lett. (2006) 47, 6369; Sousuke Hara et al., Tetrahedron Lett. (2006) 47, 1081; I. K. Mangion & D. W. C. MacMillan, J. Am. Chem. Soc. (2005) 127, 3696). Though the scope of the abovementioned reaction has been quickly extended to that of ketones (Y. Hayashi et al., Angew. Chem., Int. Ed. (2004) 43, 1112; A. Bøgevig et al., Angew. Chem., Int. Ed, (2004) 43, 1109) after the first report, there was little development in new organocatalysts (T. Kano et al., Chem. Lett. (2008) 37, 250; Y. Hayashi, et al., Adv. Synth. Catal. (2004) 346, 1435; H. Sundén et al., Tetrahedron Lett. (2005) 46, 3385; W. Wang et al., Tetrahedron Lett. (2004) 45, 7235; N. Momiyama et al., Proc. Natl. Acad. Sci. USA (2004) 101, 5374) or environmentally friendly reaction protocols (D. Font et al., Org. Lett. (2007) 9, 1943; H.-M. Guo et al., Green Chem. (2006) 8, 682).
Recently, demand has increased for innovative and imaginative synthetic methodologies to improve efficiency and sustainability such as simplicity, atom economy, reduced chemical wastage and energy usage, safety, and environment friendliness.
Accordingly, it is a further object of the present invention to provide a synthesis route to α-hydroxycarbonyl- and/or 1,2-dihydroxy compounds under conditions that are a lower burden to the environment than currently available methods.
Tetrahydro-1,2-oxazine derivatives occur frequently in biologically active compounds (Uchida, I., et al., J. Am. Chem. Soc. (1987) 109, 4108; Terano, H.; et al., J. Antibiot. (1989) 42, 145; Yu, Q.-S, et al., J. Med. Chem. (2002) 45, 3684; Katoh, T., et al., Tetrahedron (1997) 53, 10229; Judd, T. C., & Williams, R. M., Angew. Chem., Int. Ed. (2002) 41, 4683; Suzuki, M., et al., Angew. Chem. Int. Ed. (2002) 41, 4686) and are valuable synthetic intermediates (Pulz, R., et al., Org. Lett. (2002) 4, 2353; Tishkov, A. A., et al., Synlett (2002) 863; Buchholz, M.; Reissig, H.-U. Eur. J. Org. Chem. (2003) 3524; Al-Harrasi, A., & Reissig, H.-U., Angew. Chem. Int. Ed. (2005) 44, 6227; Carson, C. A., & Kerr, M. A., Angew. Chem. Int. Ed. (2006) 45, 6560). Not only do they have the potential to act as therapeutic agents and chiral building blocks, they also possess synthetic utility through reductive N—O bond cleavage to form highly functionalized 1,4-amino alcohols which can be found in a number of bioactive natural products.
The nitroso function is recognized as a unique source to prepare nitrogen- and oxygen-containing molecules. Various catalytic asymmetric reactions exploiting the unique properties of nitroso compounds (Palomo, C., et al., Angew. Chem. Int. Ed. (2007) 46, 8054), such as aminoxylation, oxyamination, and nitroso Diels-Alder reactions, have recently been developed. Nevertheless, only two general routes for tetrahydro-1,2-oxazines have so far been used including the addition of nitrones to activated cyclopropanes (M. P. Sibi, et al., J. Am. Chem. Soc. (2005) 127, 5764-5765) and the sequential nitroso aldol/Michael addition of cyclic enones reported by Yamamoto et al. (Yamamoto, Y, et al., J. Am. Chem. Soc. (2004) 126, 5962-5963; Momiyama, N, et al., J. Am. Chem. Soc. (2007) 129, 1190-1195). The substrate scope for these two examples is limited, and the development of a practical, asymmetric synthetic procedure to access enantiopure functionalized tetrahydro-1,2-oxazines from acyclic starting materials is highly desirable.
Accordingly, it is a further object of the present invention to provide a process that allows a simple formation of tetrahydro-1,2-oxazine compounds with potentially high enantio- and diastereoselectivity.